2-Arylthiazole Derivatives as CXCR3 Receptor Modulators

Abstract

The invention encompasses compounds of Formula I or pharmaceutically acceptable salts thereof, which are modulators of the CXCR3 chemokine receptor function useful for the treatment or prevention of pathogenic inflammatory processes, autoimmune diseases or graft rejection processes. Methods of use and pharmaceutical compositions are also encompassed.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         D is CR 4  or N; 
         R 3  is selected from the group consisting of: H, halo, C 1-4 alkyl, —CF 3 , —OCF 3  and —S(O) n CF 3 , wherein n is 0 or 2; 
         R 4  is selected from the group consisting of: H, halo, —OH, C 1-4 alkyl, —OCH 3 , —OCH 2 CF 3  and —CF 3 ; 
         or R 3  and R 4  may be joined together with the carbon atoms to which they are attached to form a five- or six-membered monocyclic ring, said rings containing oxygen or tetra-substituted with methyl groups as follows: 
       
       
         
           
           
               
               
           
         
         R 5  is selected from the group consisting of: —H, halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , —CF 2 CH 3 , —OCF 3  and —SCF 3 ; 
         R 6  is selected from the group consisting of —H and —OCH 3 , 
         or R 5  and R 6  may be joined together with the carbon atoms to which they are attached to form a monocyclic 5-membered ring, said ring di-substituted with methyl as follows: 
       
       
         
           
           
               
               
           
         
       
       and 
       
         
           
           
               
               
           
         
       
       is a 5 membered non-aromatic or aromatic ring or a 9 membered fused bicyclic partially aromatic or aromatic ring, each ring containing at least 1 nitrogen atom and optionally up to 3 additional heterotaoms selected from S, O and N, said rings optionally substituted with 1 to 3 substituents independently selected from the group consisting of: oxo, hydroxy, carboxy, —CF 3 , halo, —S(O) p —CH 3 , phenyl, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with carboxy or hydroxy; and
 p is 0, 1 or 2. 
 
     
     
         2 . The compound according to  claim 1  wherein: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein X, Y and Z are independently C or N, 
         R″ 2 , R″ 3 , R″ 4  and R″ 5  are independently selected from the group consisting of: —H, carboxy, —CF 3 , halo, methylthio, methylsulfonyl, phenyl, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with carboxy or hydroxy, 
         R″ 6  is H or OH, and 
         ------ is an optional double bond. 
       
     
     
         3 . The compound according to  claim 1  wherein D is N. 
     
     
         4 . The compound according to  claim 1  wherein D is CR 4 . 
     
     
         5 . The compound according to  claim 4  wherein:
 R 3  and R 4  are joined together with the carbon atoms to which they are attached to form a six-membered monocyclic ring as follows:   
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 4  wherein:
 R 3  is selected from the group consisting of H, halo, C 1-4 alkyl and —CF 3 ;   R 4  is selected from the group consisting of: H, halo, C 1-4 alkyl, —OCH 3  and —CF 3 ;   R 5  is selected from the group consisting of: H, halo, C 1-4 alkyl, CF 3  and —SCF 3 ; and   R 6  is H.   
     
     
         7 . The compound according to  claim 6  wherein:
 R 3  is selected from the group consisting of: H, Cl, Br, tert-butyl and —CF 3 ;   R 4  is selected from the group consisting of: H, Cl, Br, tert-butyl, —OCH 3  and —CF 3 ;   R 5  is selected from the group consisting of: H, Cl, Br, tert-butyl, CF 3  and —SCF 3 ; and   R 6  is H.   
     
     
         8 . The compound according to  claim 1  wherein R 6  is —H. 
     
     
         9 . The compound according to  claim 1  wherein:
 D is CR 4 ;   R 3  is selected from the group consisting of: H, Cl, Br, tert-butyl and —CF 3 ;   R 4  is selected from the group consisting of: H, Cl, Br, tert-butyl, —OCH 3  and —CF 3 ;   or R 3  and R 4  may be joined together with the carbon atoms to which they are attached to form a six-membered monocyclic ring as follows:   
       
         
           
           
               
               
           
         
         R 5  is selected from the group consisting of H, Cl, Br, tert-butyl, CF 3  and —SCF 3 ; and 
         R 6  is —H. 
       
     
     
         10 . The compound according to  claim 9  wherein:
 (1) R 3  is tert-butyl, R 4  is H and R 5  is tert-butyl;   (2) R 3  is tert-butyl, R 4  is —OCH 3  and R 5  is tert-butyl;   (3) R 3  is —CF 3 , R 4  is —H and R 5  is —CF 3 ;   (4) R 3  is H, R 4  is —OCH3 and R 5  is H;   (5) R 3  is H, R 4  is tert-butyl and R 5  is H;   (6) R 3  is H, R 4  is Cl and R 5  is H;   (7) R 3  is H, R 4  is Br and R 5  is H;   (8) R 3  is H, R 4  is —CF 3  and R 5  is H;   (9) R 3  is H, R 4  is H and R 5  is Cl;   (10) R 3  is H, R 4  is H and R 5  is Cl;   (11) R 3  is H, R 4  is H and R 5  is —CF 3 ; or   (12) R 3  is Cl, R 4  is H and R 5  is Cl.   
     
     
         11 . The compound according to  claim 9  wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein X, Y and Z are independently C or N, 
         R′ 2 , R″ 3 , R″ 4  and R″ 5  are independently selected from the group consisting of: —H, carboxy, —CF 3 , halo, methylthio, methylsulfonyl, phenyl, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with carboxy or hydroxy, 
         R″ 6  is H or OH, and 
         ------ is an optional double bond. 
       
     
     
         12 . The compound according to  claim 11  wherein: 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 9  wherein:
 D is CR 4 ;   R 3  is tert-butyl;   R 4  is H or —OCH 3 ;   R 5  is tert-butyl; and   R 6  is H.   
     
     
         14 . A compound according to  claim 1  selected from the following group:
 (1) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl}piperidin-1-yl}-2-oxoethyl)-3H-imidazo[4,5-b]pyridine;   (2) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(2,5-dimethyl-1H-imidazol-1-yl)acetyl]piperidine;   (3) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-2-methyl-1H-imidazol-5-yl]methanol;   (4) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one;   (5) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1,4-dimethyl-1,3-dihydro-2H-imidazol-2-one;   (6) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-4-methyl-1H-pyrazol-3-yl]acetate bis(hydrotrifluoroacetate);   (7) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{[4-methyl-2-(methylsulfonyl)-1H-imidazol-1-yl]acetyl}piperidine;   (8) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1,3-dihydro-2H-imidazol-2-one;   (9) Potassium — [3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetate;   (10) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-phenylimidazolidin-2-one;   (11) 3-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-3H-imidazo[4,5-b]pyridine;   (12) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1H-[(4-methoxy-1-imidazol-1-yl)acetyl]piperidine;   (13) 4-[2-(8-tert-butyl-4,4-dimethyl-3,4-dihydro-2H-chromen-6-yl)-1,3-thiazol-4-yl]-1-[(2,4-dimethyl-1H-imidazol-1-yl)acetyl]piperidine;   (14) 1-[(4-chloro-2,5-dimethyl-1H-imidazol-1-yl)acetyl]-4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidine;   (15) 3-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3H-imidazo[4,5-c]pyridine;   (16) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-imidazo[4,5-c]pyridine;   (17) 3-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3H-imidazo[4,5-b]pyridine1;   (18) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-imidazo[4,5-b]pyridine;   (19) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1-ethyl-4-methyl-1,3-dihydro-2H-imidazol-2-one;   (20) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-4-methyl-1,3-dihydro-2H-imidazol-2-one;   (21) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one;   (22) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(2-ethyl-4-methyl-1H-imidazol-1-yl)acetyl]piperidine;   (23) 2,6-di-tert-butyl-4-{4-[1-(1H-imidazo[4,5-c]pyridin-1-ylacetyl)piperidin-4-yl]-1,3-thiazol-2-yl}phenol;   (24) 2,6-di-tert-butyl-4-{4-[1-(3H-imidazo[4,5-c]pyridin-3-ylacetyl)piperidin-4-yl]-1,3-thiazol-2-yl}phenol;   (25) 2,6-di-tert-butyl-4-{4-[1-(3H-imidazo[4,5-b]pyridin-3-ylacetyl)piperidin-4-yl]-1,3-thiazol-2-yl}phenol;   (26) 2,6-di-tert-butyl-4-(4-{1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidin-4-yl}-1,3-thiazol-2-yl)phenol;   (27) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-4-methyl-1H-imidazol-5-yl]methanol;   (28) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{2-(methylthio)-1H-imidazol-1-yl]acetyl}piperidine;   (29) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{2-(methylsulfonyl)-1H-imidazol-1-yl]acetyl}piperidine;   (30) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl) 5-methyl-1H-imidazol-4-yl]acetic dihydrochloride;   (31) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)-4-methyl-1H-imidazol-5-yl]acetic dihydrochloride;   (32) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidine;   (33) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidine;   (34) 4-[2(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(4-methyl-1-imidazol-1-yl)acetyl]piperidine;   (35) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(5-methyl-1-imidazol-1-yl)acetyl]piperidine;   (36) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-methylimidazolidin-2-one;   (37) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)-1,3-oxazolidin-2-one;   (38) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]piperidine;   (39) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]piperidine;   (40) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-pyrrolo[2,3-b]pyridine;   (41) 1-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-1H-pyrrolo[2,3-b]pyridine;   (42) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-benzimidazole;   (43) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-2-methyl-1H-benzimidazole;   (44) 2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-1H-benzimidazole;   (45) 1-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-2-methyl-1H-benzimidazole;   (46) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine;   (47) 1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidine;   (48) 4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidine;   (49) 1-[(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidine;   (50) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)imidazolidin-2-one;   (51) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)-1H-imidazol-2-yl]metanol;   (52) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-benzimidazol-2-yl]metanol;   (53) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{[2-(trifluoromethyl)-1H-imidazol-1-yl]acetyl}piperidine;   (54) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{[2-methyl-1H-imidazol-1-yl]acetyl}piperidine;   (55) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-(1H-imidazol-1-ylacetyl)piperidine;   (56) [1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-5-methyl-1H-pyrazol-3-yl]acetic acid;   (57) Potassium (1-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl)-5-methyl-1H-pyrazol-3-yl)acetate;   (58) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-[(2,4-dimethyl-1H-imidazol-1-yl)acetyl]piperidine;   (59) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (60) 3-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridine;   (61) 4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidine;   (62) 3-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-3H-imidazo[4,5-c]pyridine;   (63) 1-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-1H-imidazo[4,5-c]pyridine;   (64) 1-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-2-methyl-1H-imidazo[4,5-c]pyridine;   (65) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-imidazole-2-carboxylic acid dihydrochloride;   (66) 1-ethyl-3-{2-oxo-2-{4-(2-phenyl-1,3-thiazol-4-yl)piperidin-1-yl]ethyl}-1,3-dihydro-2H-imidazol-2-one;   (67) 1-ethyl-3-(2-{4-[2-(4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1,3-dihydro-2H-imidazol-2-one;   (68) 1-(2-{4-[2-(4-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (69) 1-(2-{4-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (70) 1-(2-{4-[2-(4-bromophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (71) 1-(2-{4-[2-(4-trifluoromethylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (72) 1-(2-{4-[2-(3-chlorophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (73) 1-(2-{4-[2-(3-bromophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (74) 1-(2-{4-[2-(3-trifluoromethylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;   (75) 1-(2-{4-[2-(3,5-dichlorophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one; and   (76) 1-ethyl-3-{2-oxo-2-[4-(2-pyridin-4-yl-1,3-thiazol-4-yl)piperidin-1-yl]ethyl}-1,3-dihydro-2H-imidazol-2-one.   
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
         16 . A method for treating a disease or condition mediated by the CXCR3 chemokine receptor comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         17 . The method according to  claim 16  wherein the disease or condition is selected from the group consisting of: acute and chronic transplant rejection, psoriasis, rheumatoid arthritis and multiple sclerosis.